JP4981446B2 - New production method of 2H-chromenes - Google Patents

Description

The present invention relates to a novel process for the preparation of 2H-chromenes, in particular the compound of formula I below (Ikraprim) and valuable intermediates of this process.

The compounds of formula I have valuable antibiotic action. This compound can be used for the control or prevention of infectious diseases in humans and non-human mammals. In particular, it exhibits a broad spectrum of antibacterial activity including multidrug resistant pathogens. This compound can also be administered in combination with known substances with antibacterial action and is synergistic with some of them.

Typical combination partners include, for example, sulfonamides as well as other inhibitors of enzymes involved in folic acid biosynthesis, such as pteridine derivatives.

The current production method of Compound I is described in US Pat. No. 5,773,446 (see Patent Document 1). The disadvantage of this synthesis method is that the synthesis route is long and as a result the overall yield is low. Most of the intermediates are not crystalline, which makes this synthetic method less economically attractive as an industrial process. In addition, some expensive reagents cannot be recovered.

The problem is further complicated by the use of a halide solvent, such as methylene chloride. Halide solvents are expensive to handle and properly process, thus incurring additional costs.
US Pat. No. 5,773,446

Therefore, there is a need for a process for preparing compounds of Formula I with higher overall yield and reduced number of reaction product isolation steps. What is also needed is a method in which all of the isolated intermediate is crystalline and does not require chromatography.

In the present invention, a compound of formula 1 is reacted with a compound of formula 9 to obtain a compound of formula 2, which is hydrolyzed to a compound of formula 3, which is then reduced to a compound of formula 4. or, Oh Rui provides a process for the preparation of a compound of formula I a compound according to obtain the compound of formula 5 is reacted with a compound of formula 9 of the formula 6 (see scheme 1 below).

The compound of formula 5 prepared according to the above reaction steps is a central intermediate in the preparation of the compound of formula I. It can be mentioned that the compounds of formulas 2 and 5 do not need to be isolated. It is also possible to react a common reactant, ie a compound of formula 9, with a compound of formula 1 or a compound of formula 6 in an alkaline reaction medium in which neither ester 1 nor aldehyde 6 appears to be stable. Seems to be surprising.

A compound of formula 5 can be converted to a compound of formula I by reacting a compound of formula 5 with a compound of formula 10 to give a compound of formula 11 that can be converted to a compound of formula I ( Scheme 3).

The preparation of the central intermediate of formula 5 is shown in Scheme 1 and the common intermediate 9 is synthesized from the commercially available compound 7 as shown in Scheme 2.

The compounds of formula I are basic in nature and can be converted, if desired, by acid to pharmaceutically acceptable acid addition salts. Suitable acids are, for example, hydrochloric acid, maleic acid, methanesulfonic acid and lactic acid. More preferred is methanesulfonic acid.

In this synthesis method, a racemate of the compound of formula I is obtained. However, if desired, the racemate can be resolved in a manner known per se, for example by crystallization or chromatography in the presence of an optically active acid.

The method of the present invention provides a number of advantages and improvements over current methods of synthesizing aldehydes of formula 5 and subsequent methods of synthesizing iclaprim of formula I. Corresponding starting materials of formulas 1, 6 and 7 are commercially available in large quantities.

To prepare compounds of formula I, the central intermediate of formula 5 can be prepared according to the sequence of reactions A1, B1, C1 and D1. Cyclization A1 comprises a compound of formula 1 together with a compound of formula 9 in a high-boiling inert solvent such as toluene, p-xylene and the like such as 3-picoline, N, N; N ′, N′-tetramethylethylenediamine Can be carried out by heating to about 100 ° -170 ° C. The saponification B1 of ester 2 can be carried out in an alcohol, such as methanol, isopropanol or acetone-isopropanol mixture, at room temperature or up to 60 ° C., using an alkali hydroxide such as sodium hydroxide or potassium hydroxide. . Reduction C1 of compound 3 can be carried out in an inert solvent such as tertiary butyl methyl ether (TBME), tetrahydrofuran, toluene or toluene-TBME mixture at room temperature or slightly elevated temperature up to 50 ° C., for example lithium aluminum hydride, Preference is given to using dihydridobis (2-methoxyethoxy) sodium aluminate (Red-Al) . Of oxidation D1 of compound 4, for example in dimethyl sulfoxide, sulfur trioxide - using pyridine complex and triethylamine can be carried out at 0 ° to 20 ° C..

Compounds of formula 5 can also be prepared by the reaction sequence shown in Scheme 1. Cyclization A2 comprises the compound of formula 6 together with the compound of formula 9 in a high-boiling inert solvent such as toluene, p-xylene and the like, such as 3-picoline, N, N; N ′, N′-tetramethylethylenediamine Can be carried out by heating at about 100 ° to 170 ° C. in the presence of. The reaction of aldehyde 6 at high elevated temperature under basic conditions is rather unexpected because aldehydes tend to polymerize under similar conditions.

The preparation of the compound of formula 9 can be carried out according to the order of reactions A3 and B3 as shown in Scheme 2. The magnesium bromide salt of cyclopropylacetylene (compound 7) as an intermediate is obtained by adding lower alkyl bromide (eg ethyl, butyl or cyclohexyl) magnesium at 30 ° -80 ° C. in an inert solvent such as tetrahydrofuran or toluene. Manufactured by. Condensation of the anion of compound 7 with a trialkyl orthoformate, such as trimethyl orthoformate or triethyl orthoformate, occurs at 50 ° -120 ° C. by gradually distilling off the solvent. Hydrogenation of compound 8 according to step B3 is performed at room temperature or 60 ° C. in the presence of a Lindlar catalyst poisoned with, for example, 3,6-dithia-1,8-octanediol in an inert solvent such as ethyl acetate. Can be carried out by reaction of compound 8 under elevated temperature of up to 1-5 bar hydrogen pressure.

The compounds of formulas 3 and 4 are novel and the compounds of formula 3 are also the subject of the present invention. They can be prepared according to the reaction sequence shown in Scheme 1. The preparation of the compounds outlined in Schemes 1, 2 and 3 is further described in more detail in the examples.

As already mentioned, the compounds of formula I or their pharmaceutically acceptable salts have valuable antibiotic action. This compound is active against many pathogenic microorganisms such as S. aureus, P. carinii, due to its bacterial dihydrofolate reductase (DHFR) inhibitory activity . The activity of this compound G. Hartman et al., Abstract F2020, 42nd Interscience Conference on Antibacterials and Chemotherapy, San Diego, California, September 27-30, 2002; American Microbiological Society, Washington, DC, 2002 Yes.

Other objects, advantages and novel features of the invention will become apparent to those skilled in the art from consideration of the following examples, which are not intended to limit the scope of the invention.

The following examples illustrate the invention in more detail. Examples 1-6 describe the preparation of compound 5, examples 7 and 8 describe the preparation of the compound of formula 9, and examples 9 and 10 are the final of formula I of the compound of formula 5. Describes conversion to a product (Ikraprim). The temperature is given in degrees Celsius.

Compounds of Formula 1 can be synthesized, for example, according to M Tanaka et al., Tetrahedron, 51, 11703 (1995). Compounds of formula 6 are described, for example, by AK Sinhababu et al. Org. Chem., 48, 1941-1944 (1983). Compound 7 is, for example, S.I. E. It can be prepared according to Schmidt et al., Synlett, 12, 1948-1950 (1999). All other reagents and solvents are commercially available and are readily available from, for example, Fluka or equivalent commercial suppliers.

TBME Tertiary butyl methyl ether IPAc Isopropyl acetate DMSO Dimethyl sulfoxide RT Room temperature Red-Al Dihydridobis (2-methoxyethoxy) aluminate THF Tetrahydrofuran

Example 1
This example illustrates the preparation of 2-cyclopropyl-7,8-dimethoxy-2H-chromene-5-carboxylic acid methyl ester 2 (step A1).
3-Hydroxy-4,5-dimethoxy-benzoic acid methyl ester 1 (20 g, 94
mmol) and cis- (3,3-dimethoxy-propenyl) -cyclopropane 9 (22.3 g, 90% purity, 141 mmol) were dissolved in 70 ml of p-xylene and 3-picoline (3.6 ml, 37. 6 mmol) was added.
The mixture was heated to the reflux temperature (oil bath 160 ° C.), and the produced methanol was removed by a distillation head.
In order to specifically remove the produced methanol, a heating reflux condenser having a temperature between the reaction vessel and the distillation head of 70 ° C. was used. After 24 hours, xylene and unreacted acetal were distilled off from the reaction mixture. This dark oil was used directly in the next step.

Isolation of 2 is possible, for example, by crystallizing 2.6 g of 2 after cooling (−20 ° C., 18 hours) from methylcyclohexane / TBME (3: 1, 10 ml). 1.07 g of pure 2 was isolated as a white yellow solid.
¹ H-NMR (CDCl ₃ ) δ (ppm): 7.25 (dd, 1H, J ₁ = 10.1 Hz, J ₂ = 1.5 Hz); 7.09 (s, 1H, C6H); 5.8 _{(dd, 1H, J 1 =} 10.1Hz, J 2 = 4.0Hz); 4.24 (ddd, 1H, J 1 = 8.6Hz, J 2 = 4.0Hz, J 3 = 1.5Hz); 3.95 (s, 3H, OCH ₃ ); 3.88 (s, 6H, 2 × OCH ₃ ); 1.2-1.3 (m, 1H,), 0.32-0.62 (m, 4H); mp .: 61 ° C.

Example 2
This example illustrates the preparation of 2-cyclopropyl-7,8-dimethoxy-2H-chromene-5-carboxylic acid 3 (step B1).
Crude product 2 (14.1 g, 60% content, 29.2 mmol) was dissolved in 135 ml isopropanol / acetone (5: 1) and 29 ml 4N NaOH solution was added. The reaction mixture was stirred at room temperature for 30 minutes and at 50 ° C. for 1 hour. The solution was then evaporated and the residue was dissolved with 100 ml of water and treated with charcoal to remove impurities and polymerization products. After filtration, the aqueous layer was extracted twice with 100 ml TBME. Isopropyl acetate was added to the aqueous phase. The pH of this solution was adjusted to pH = 1 with concentrated hydrochloric acid. After separation, the aqueous phase was extracted twice with 100 ml IPAc and the combined organic phases were concentrated to dryness. The oil was crystallized from IPAc / heptane. The compound of formula 3 (7.8 g) was isolated as light brown crystals.
¹ H-NMR (CDCl ₃ ) δ (ppm): 7.44 (dd, 1H, J ₁ = 10.36 Hz, J ₂ = 1.52 Hz); 7.23 (d, 1H); 5.86 (dd , 1H, J ₁ = 10.36 Hz, J ₂ = 3.8 Hz); 4.26 (ddd, 1H, J ₁ = 8.32 Hz, J ₂ = 3.8 Hz, J ₃ = 1.76 Hz); _{98 (s, 3H, OCH 3} ); 3.9 (s, 3H, OCH 3); 1.33-1.23 (m, 1H, CH), 0.33-0.64 (m, 4H); mp .: 124-126.5 ° C.

Example 3
This example illustrates the preparation of (2-cyclopropyl-7,8-dimethoxy-2H-chromen-5-yl) -methanol 4 (step C1).
LiAlH ₄ (0.85 g, 0.8 eq, 22.6 mmol) was added to a solution containing acid 3 (7.8 g, 28.2 mmol) in anhydrous THF (150 ml) at 15 ° C. under an argon atmosphere. did. The mixture was then allowed to warm to room temperature and then stirred at 50 ° C. for 1 hour.
Quenching and work-up were performed by adding 2.5 ml of water containing 0.85 ml of water and 0.85 g of NaOH. The precipitated aluminate was filtered and the organic phase was concentrated to dryness. Crude compound 4 was obtained as a light brown solid (usually in quantitative yield), which was used further as it was.
A sample was crystallized from methylcyclohexane / TBME (1: 1) and subjected to a sample for NMR:
¹ H-NMR (CDCl ₃ ) δ (ppm): 6.65 (d, 1H, J = 10.1 Hz), 6.48 (s, 1H); 5.73 (dd, 1H, J ₁ = 10. 4.64 (s, 2H); 4.2-4.26 (m, 1H); 3.88 (s, 3H, CH ₃ ); 3.84 (s, 3H, 1 Hz, J ₂ = 4 Hz); CH ₃ ); 1.73 (bs, 1H, OH); 1.21-1.31 (m, 1H, CH), 0.31-0.61 (m, 4H); mp .: 94-96 ° C. .

Example 4
This example illustrates the preparation of (2-cyclopropyl-7,8-dimethoxy-2H-chromen-5-yl) -methanol 4 (step C1).
Acid 3 (5.7 g, 20.7 mmol) was dissolved in anhydrous TBME / toluene (1: 1, 100 ml) and Red-Al (9.2 ml, 3.5-M in toluene) in 15 ml of toluene. , 32.1 mmol) was added over 20 minutes. The temperature was kept at 30 ° C. during the addition. The reaction mixture was stirred at 50 ° C. for 90 minutes, then poured into ice water and acidified with 2.5-N sulfuric acid. After extracting the product with TBME, the organic layer was washed with brine, 0.1-N NaOH, brine. After drying over magnesium sulfate and evaporation of the solvent, 4 (4.8 g, 18.3 mmol) was obtained as a pale yellow solid.
A sample was crystallized from methylcyclohexane / TBME (1: 1) and subjected to a sample for NMR:
¹ H-NMR (CDCl ₃ ) δ (ppm): 6.65 (d, 1H, J = 10.1 Hz), 6.48 (s, 1H, C6H); 5.73 (dd, 1H, J ₁ = 10.1 Hz, J ₂ = 4 Hz); 4.64 (s, 2H, CH ₂ ); 4.2-4.26 (m, 1H); 3.88 (s, 3H, CH ₃ ); 3.84 (s, 3H, CH ₃ );
1.73 (bs, 1H, OH); 1.21-1.31 (m, 1H, CH), 0.31-0.61 (m, 4H); mp .: 94-96 ° C.

Example 5
This example illustrates the preparation of 2-cyclopropyl-7,8-dimethoxy-2H-chromene-5-carbaldehyde 5 (step D1).
A 20 ml toluene solution of sulfur trioxide-pyridine complex (17 g, 107 mmol), 7.5 ml DMSO and 17 ml triethylamine is cooled to 10 ° C. Then 4 (11.2 g, 42.7 mmol) in 15 ml toluene is slowly added. After stirring at 20 ° C. for 5 hours, 40 ml of water was then added and the reaction mixture was stirred overnight at room temperature. The aqueous phase was extracted with toluene (3 times, 20 ml) and the combined organic phases were concentrated to dryness. A brown-orange oil was obtained in quantitative yield and used in the next step.
A sample was crystallized from methylcyclohexane / TBME (1: 1) and subjected to a sample for NMR:
¹ H-NMR (CDCl ₃ ) δ (ppm): 10.11 (s, 1H, CHO); 7.31 (d, 1H, J = 10.1 Hz); 6.9 (s, 1H); _{91 (dd, 1H, J 1} = 10.1, J 2 = 3.5Hz); 4.24-4.29 (m, 1H); 3.98 (s, 3H, OCH 3); 3.9 ( _{s, 3H, OCH 3);} 1.21-1.31 (m, 1H, CH); 0.32-0.62 (m, 4H); mp: 44-47 ℃.

Example 6
This example illustrates the preparation of 2-cyclopropyl-7,8-dimethoxy-2H-chromene-5-carbaldehyde 5 (step A2).
Compound 6 (5 g, 27.4 mmol) and cis- (3,3-dimethoxy-propenyl) -cyclopropane 9 (7.6 g, 90% purity, 48 mmol) were dissolved in 33 ml of p-xylene and then 3- Picolin (0.64 g, 6.8 mmol) was added. The mixture was heated to reflux temperature (160 ° C. in an oil bath) under an argon atmosphere, and the produced methanol was removed with a distillation head. In particular, only methanol was removed using a heating reflux condenser having a temperature of 75 ° C. between the reaction vessel and the distillation head. After 25 hours, the reaction mixture was cooled to room temperature and then ethyl acetate (400 ml) was added. The mixture was then washed with 0.1 N HCl (2 times 50 ml) and 1 N NaOH solution (2 times 50 ml). The organic solution was then dried over magnesium sulfate and concentrated under reduced pressure. A dark brown oil (7.9 g) was obtained. The oil was then distilled (Kugelrohr distillation apparatus) to give 4.8 g (80% purity, 14.7 mmol) of a yellow oil (bp 220-240 ° C., 0.5 mm bar). .
¹ H-NMR (CDCl ₃ ) δ (ppm): 10.11 (s, 1H, CHO); 7.31 (d, 1H, J = 10.1 Hz); 6.9 (s, 1H); _{91 (dd, 1H, J 1} = 10.1, J 2 = 3.5Hz); 4.24-4.29 (m, 1H); 3.98 (s, 3H, OCH 3); 3.9 ( _{s, 3H, OCH 3);} 1.21-1.31 (m, 1H, CH); 0.32-0.62 (m, 4H).

Example 7
This example illustrates the preparation of (3,3-dimethoxy-1-propynyl) -cyclopropane 8 (step A3).
Magnesium (26,7 g, 1.1 mol) is suspended in 350 ml of tetrahydrofuran and then ethyl bromide (74.6 ml, 1 mol) is added at a rate such that the tetrahydrofuran is continuously refluxed. did. After the addition was complete, the mixture was stirred at 50-60 ° C. for 1 hour to complete the reaction. After cooling to room temperature, ethynylcyclopropane 7 (80.6 ml, 70% in toluene, 0.95 mol) was slowly added to the Grignard reagent for 30 minutes (ethane evolved). After the addition, the mixture was further stirred at room temperature for 1 hour, and then trimethyl orthoformate (120, 3 ml, 1.1 mol) and toluene (400 ml) were added. The mixture was heated (oil bath temperature 100 ° -120 ° C.) and then tetrahydrofuran was removed by distillation for 4 hours. After cooling to room temperature and stirring overnight, TBME (500 ml) was added to dilute the reaction mixture and water was added slowly (50 ml). The clear organic solution was decanted from high viscosity magnesium hydroxide.
Magnesium hydroxide was extracted twice more with TBME (2 times 100 ml) and the combined organic solution was dried over magnesium sulfate, filtered and concentrated. Compound 8 was isolated by vacuum distillation (10 mbar, bp: 55 ° C.-60 ° C., 99 g, 0.7 mol).
¹ H-NMR (CDCl ₃ ) δ (ppm): 5.09 (d, 1H, J = 1.5 Hz, CH); 3,33 (s, 6H, 2 × CH ₃ ); 1.22-1. 32 (m, 1H, CH) , 0.71-0.81 (m, 4H, 2 × CH 2).

Example 8
This example illustrates the preparation of (3,3-dimethoxy-propenyl) -cyclopropane 9 (step B3).
(3,3-Dimethoxy-1-propynyl) -cyclopropane 8 (40 g, 0.28 mol) was dissolved in ethyl acetate (500 ml), Lindlar catalyst (5 g, 5% Pd “Fluka”) and 3 mg of 3 1,6-dithia-1,8-octanediol was added.
The reaction vessel was evaporated and set 3 times under hydrogen atmosphere, then placed under hydrogen pressure (˜1 bar) and the suspension was stirred vigorously for about 2.5 hours until the calculated hydrogen volume was removed. . The mixture was filtered and concentrated under reduced pressure until the starting material disappeared. Except for the presence of some ethyl acetate, product 9 is pure by ¹ H-NMR. This was used in the next reaction based on 90% purity without further treatment.
¹ H-NMR (CDCl ₃ ) δ (ppm): 5.22 (dd, 1H, J ₁ = 11 Hz,
J ₂ = 6.5 Hz, CHCH (OCH ₃ ) ₂ ); 5.22 (dd, 1H, J ₁ = 6.5 Hz, J ₃ = 1 Hz, CHCH (OCH ₃ ) ₂ ); 4.98 (dd, J _{1 = 11Hz, J 3 = 1Hz} ,
CH); 3.35 (s, 6H, 2 × OCH ₃ ), 1.6-1.75 (m, 1H, CH), 0.75-0.81 (m, 2H, CH ₂ ), 0.8. _{38-0.4 (m, 2H, CH 2} ).

Example 9
This example illustrates the preparation of 2- (2-cyclopropyl-7,8-dimethoxy-2H-chromen-5-ylmethyl) -3-phenylamino-acrylonitrile 11 (step A4).
Aldehyde 5 (3.75 g, 80% purity, 11.5 mmol) and fresh crystallized 3-anilinopropionitrile (1.9 g, 13 mmol) were dissolved in DMSO (20 ml) under a nitrogen atmosphere at 10 ° C. It was. Potassium tert-butoxide (1.7 g, 16 mmol) was added in small portions to the reaction mixture at 10 ° C. After the addition, the mixture was allowed to warm to room temperature and then stirred for 3 hours. The color of the solution changed from yellow to dark brown. Then 50 ml of cold water was added and the mixture was then extracted with ethyl acetate (3 times 100 ml). The organic layers were combined and washed with brine (twice, 100 ml) and dried over magnesium sulfate. Activated charcoal was added to the solution to remove color and the mixture was stirred for 30 minutes and then filtered. The solvent was removed to give 5.2 g of a dark brown oil that was normally used further without isolation.
Crystallization from ethanol / hexane (1: 1) gave 11 (2.2 g, 5.67 mmol) as a mixture of cis / trans isomers.
The mother liquor still contained a lot of eleven.
Cis-compound: ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.2.7.34 (m, 3H, aniline), 6.9-7.02 (m, 1H, aniline), 6.79 (d, 2H, aniline), 6.68 (d, 1H, J = 12.6 Hz, CH); 6.54 (d, 1H, J = 10.1 Hz); 6.34 (s); 5.75 (dd, 1H, J ₁ = 10.1 Hz, J ₂ = 4 Hz); 4.23-4.27 (m, 1H); 3.9 (s, 3H, OCH ₃ ); 3.85 (s, 3H , OCH ₃ ); 3.47 (s, 2H, CH ₂ ), 1.56 (bs, 1H, NH); 1.18-1.29 (m, 1H, CH); 0.3-0.6 (m, 4H).
Trans-compound: ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.2.7.34 (m, 3H, aniline), 6.9-7.02 (m, 1H, aniline), 6.74 (d, 2H, aniline); 6.60 (d, 1H, J ₁ = 10.1 Hz, C4H); 6.43 (s); 6.28 (d, 1H, J = 12.6 Hz, CH); _{5.80 (dd, 1H, J 1} = 10.1Hz, J 2 = 4Hz);
4.23-4.27 (m, 1H, C2H) ; 3.9 (s, 3H, OCH 3); 3.85 (s, 3H, OCH 3); 3.53 (s, 2H, CH 2) 1.56 (bs, 1H, NH); 1.18-1.29 (m, 1H, CH); 0.3-0.6 (m, 4H).

Example 10
This example illustrates the preparation of a compound of formula I (step B4).
Guanidine hydrochloride (1.62 g, 17 mmol) was suspended in absolute ethanol (20 ml), and potassium tertiary butoxide (1.9 g, 17 mmol) was added. The mixture was stirred for 15 minutes, then filtered and the filter cake was washed once with ethanol (10 ml). The combined filtrate was added to a suspension of 11 (2.2 g, 5,67 mmol) in ethanol (20 ml) and the reaction mixture was heated to 85 ° C. for 8 hours under an argon atmosphere, by which time no more 11 Was not detected by HPLC.
The reaction mixture was concentrated under reduced pressure to a volume of 25 ml and cooled to 4 ° C. The crystallized I was filtered off, washed with cold ethanol and dried under vacuum (1.7 g, 4.8 mmol).
¹ H-NMR (D ₆ -DMSO) δ ppm): 7.07 (s, 1H, CH-pyrimidine), 6.45 (d, 1H, J = 10 Hz, C4H); 6.42 (s, 1H); 6.17 (bs, 2H, NH ₂ ); 5.7 (dd, 1H, J ₁ = 10 Hz, J ₂ = 4 Hz); 5.65 (bs, 2H, NH ₂ ); 4.2-4.3 (m, 1H); 3.73 ( s, 3H, OCH 3); 3.70 (s, 3H, OCH 3), 3.5 (s, 2H, CH 2);
1.06-1.2 (m, 1H, CH); 0.26-0.54 (m, 4H), mp .: 226-227 ° C.

Claims (6)

A process for the preparation of a compound of formula I or a pharmaceutically acceptable salt thereof comprising the following (a) and (d):

(A) reacting a compound of formula 1 with a compound of formula 9 to obtain a compound of formula 2, which is hydrolyzed to a compound of formula 3, which is then reduced to a compound of formula 4; Oxidize to give a compound of formula 5 and

(D) reacting a compound of formula 5 with a propionitrile of formula 10 to obtain a compound of formula 11 which converts the compound of formula 5 into a compound of formula I, which is reacted with guanidine to give a compound of formula I Or a pharmaceutically acceptable salt thereof.

A process for the preparation of a compound of formula I comprising the following (c) and (d) or a pharmaceutically acceptable salt thereof:

(C) reacting a compound of formula 6 with a compound of formula 9 to obtain a compound of formula 5; and

(D) reacting a compound of formula 5 with a propionitrile of formula 10 to obtain a compound of formula 11 which converts the compound of formula 5 into a compound of formula I, which is reacted with guanidine to give a compound of formula I Or a pharmaceutically acceptable salt thereof.

The method according to claim 1 or 2, a method wherein the compound of Formula 2, 5 and 11 are used for isolation by Rukoto without subsequent step. A process for the preparation of a compound of formula 5 comprising:

(A) reacting a compound of formula 1 with a compound of formula 9 to obtain a compound of formula 2, which is hydrolyzed to a compound of formula 3, which is then reduced to a compound of formula 4; consists of obtaining a compound of formula 5 by oxidizing.

A process for the preparation of a compound of formula 5 comprising:

(C) reacting a compound of formula 6 with a compound of formula 9 to obtain a compound of formula 5.

A compound of formula 3.